CN102369010A - 用于乳腺癌的利用奈拉替尼的治疗方案 - Google Patents
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Abstract
描述了用于治疗过表达/扩增HER-2/neu的癌症的扩展方案，其包括在完成手术和辅助治疗之后将奈拉替尼治疗过程递送至过表达/扩增HER-2/neu的癌症患者。奈拉替尼方案可持续长达12个月至5年。还提供了经设计用以促进对方案的顺从性的药物试剂盒。
Description
发明背景
乳腺癌是妇女中诊断频率最高的恶性肿瘤并且是全世界妇女中癌症死亡率的首要原因。乳腺癌的全球发病率据估计在下一个十年达到5百万妇女[Parkin，DM和Fernandez LM，Use of statistics to assessthe global burden of breast cancer.Breast Journal.2006；(12，Suppl 1)：S70-80；World Health Statistics.2008，世界卫生组织]。在2007年，乳腺癌在世界范围导致大约540,000例死亡[World HealthOrganization Fact Sheet No.297.2008；可从WHO网站获得]。
TKI(酪氨酸激酶抑制剂)的erbB(成红细胞白血病病毒癌基因同源物)家族由4个成员组成：erbB-1(EGFR[表皮生长因子受体])、erbB-2(HER-2，neu)、erbB-3(HER-3)和erbB-4(HER-4)。受体的erbB家族参与细胞增殖、肿瘤发生和转移，并且在多个肿瘤类型中异常表达。HER2-阳性的乳腺癌，即，对于称为人EGFR的蛋白质检测为阳性的乳腺癌，与Erb-2-蛋白过表达相关，或乳腺癌肿瘤中erbB-2基因的扩增与更具侵袭性的临床疾病和更糟的预后相关[Slamon D，Humanbreast cancer：correlation of relapse and survival withamplification of the HER-2/neu oncogene.Science.1987(235)：177-182]。
曲妥珠单抗，选择性结合人erbB-2受体的人源化单克隆抗体，改善了患有erbB-2-阳性乳腺癌的妇女的预后。在患有过表达erbB-2的转移性乳腺癌的患者中，与化学治疗组合的曲妥珠单抗，与单独的化学治疗相比较，促进肿瘤消退，延长肿瘤进展的时间和延长中位存活(median survival)，从而导致其被批准为转移背景中的一线疗法。[Ligibel JA和Winer EP，trastuzumab/chemotherapy combinationsin metastatic breast cancer.Seminars in Oncology.2002；29(3Suppl 11)：38-43]。赫赛汀(曲妥珠单抗)[Package insert，Genentech(2008)]。曲妥珠单抗也被批准与用于治疗过表达erbB-2的淋巴结阳性或淋巴结阴性(雌激素受体/孕酮受体[ER/PgR]阴性)转移性乳腺癌的其他药物组合用于辅助背景。因此，曲妥珠单抗已被用作治疗方案的部分，所述治疗方案由下列组成：(a)多柔比星，环磷酰胺，以及紫杉酚或多西他赛，(b)利用多西他赛和卡铂的方案，和(c)在基于多模式蒽环类抗生素的治疗后作为单一试剂。
在确诊HER+乳腺癌后目前的护理标准是手术，然后进行一年的辅助治疗。标准辅助治疗是ER/PR阳性疾病的激素治疗、化学治疗、辐射与曲妥珠单抗的一些组合。尽管完成了辅助治疗，但早期乳腺癌患者仍然处于复发的风险中。曲妥珠单抗治疗的公开报导显示，无疾病存活率为3年的80.6％[Smith I等人2-year follow-up of trastuzumabafter adjuvant chemotherapy in HER2-positive breast cancer：arandomized controlled trial.Lancet.2007；369：29-36]至4年的85.9％至82％[Perez EA等人，Updated results of the combinedanalysis of NCCTG N9831and NSABP B-31adjuvant chemotherapywith/without trastuzumab in patients with HER2-positive breastcancer.Journal of Clinical Oncology.ASCO Annual MeetingProceedings.2007；25(18S)：512，和Slamon D等人，Phase III trialcomparing AC-T with AC-TH and with TCH in the adjuvant treatmentof HER2positive early breast cancer patients：second interimefficacy analysis.Presentation by Slamon D.SABCC 2006]。
已描述了HKI-272(奈拉替尼)用于肿瘤的治疗[美国专利6,288,082]。奈拉替尼(neratinib)是有效的、不可逆的泛erbB抑制剂。奈拉替尼为口服可用的小分子，其在胞内酪氨酸激酶结构域上抑制erbB-1、erbB-2和erbB-4，作用机制与曲妥珠单抗不同。奈拉替尼降低erbB-1和erbB-2自磷酸化、下游信号转导以及erbB-1和erbB-2依赖性细胞系的生长。临床前数据表明，奈拉替尼在表达erbB-1和/或erbB 2的癌细胞系中具有抗肿瘤活性，细胞IC50＜100nM[RabindranSK等人.Antitumor activity of HKI-272，an orally active，irreversible inhibitor of the HER-2tyrosine kinase.CancerResearch.2004；64(11)：3958-65]。
所需要的是提高患者存活率的药物和方案和/或在基本治疗(primary treatment)和辅助治疗完成后减少乳腺癌复发的药物和方案。
发明概述
在一个方面中，本发明提供了用于治疗过表达/扩增HER-2/neu的肿瘤的方案，其包括将奈拉替尼治疗过程作为曲妥珠单抗辅助治疗的延伸，递送至过表达/扩增HER-2/neu的癌症患者，例如，在完成手术和标准辅助治疗之后递送奈拉替尼。
在另一个方面中，本发明提供了用于降低患者的过表达/扩增HER-2/neu的乳腺癌的复发率(与只接受基本治疗和曲妥珠单抗辅助治疗的患者相比较)的方法或方案。该方法包括在基本治疗和利用曲妥珠单抗的标准辅助治疗之后将奈拉替尼递送至所述患者。在一个实施方案中，所述方法还在一个或多个常规新辅助疗法或标准辅助治疗完成之后进行。
在另一个方面中，本发明提供了用于改善无侵袭性疾病存活(invasive disease free survival)的方案，其包括在完成基本治疗和利用曲妥珠单抗的标准辅助治疗后，用奈拉替尼治疗癌症患者。在一个实施方案中，利用奈拉替尼的治疗在手术后和利用曲妥珠单抗的标准辅助治疗后2周至48个月内开始。
根据下列发明详述，本发明的其他方面和优点将变得显而易见。
发明详述
在一个实施方案中，本发明提供了用于治疗过表达/扩增HER-2/neu的癌症的扩展的辅助方案，其包括将奈拉替尼治疗过程递送至过表达/扩增HER-2/neu的癌症患者。这样的扩展辅助治疗包括，在利用曲妥珠单抗的辅助治疗完成后开始奈拉替尼治疗。该扩展辅助治疗用于提供改善的无侵袭性疾病存活(IDFS)或无疾病存活(DFS)-原位导管癌(DCIS)和/或改善总存活(overall survival)、远处复发的时间(time to distant recurrence)和/或无远处疾病存活(distantdisease-free survival)。
如本文中所使用的，无侵袭性疾病存活(IDFS)被定义为从随机化的日期至IDFS事件的日期的时间，所述IDFS事件包括：侵袭性同侧乳腺肿瘤复发、局部/区域性侵袭性复发、远处复发(distantrecurrence)、任何原因引起的死亡、侵袭性对侧乳腺癌和第二原发性侵袭性癌(非乳腺)。DFS-DCIS被定义为从随机化至任何IDFS事件或原位导管癌的第一次发生的时间。无远处疾病存活(DDFS)为从随机化至第一次远处复发或任何原因引起的死亡的时间。远处复发的时间(TTDR)被定义为随机化与第一次远处肿瘤复发的日期之间的时间，不考虑局部复发和第二乳腺癌或非乳腺癌，并且把远处乳腺癌复发之前的死亡考虑为设限事件(censoring event)。
因此，利用奈拉替尼的本发明的扩展辅助治疗通过减少复发或死亡的风险而增加无疾病存活。在一个实施方案中，扩展奈拉替尼辅助治疗，与曲妥珠单抗治疗后的常规观察相比较，减少癌症复发或死亡的危险，即风险率，30％或20％。
在另一个实施方案中，通过使用本文中描述的扩展奈拉替尼方案，少于15％，少于10％和/或少于5％的已接受基本治疗和辅助治疗的患者在治疗开始后3年患癌症。在另一个实施方案中，通过使用本文中描述的扩展奈拉替尼方案，少于20％，少于15％和/或少于5％的已接受基本治疗和辅助治疗的患者在治疗开始后5年患癌症。
如本文中所使用的，奈拉替尼是指HKI-272，其具有下列核心结构：
以其游离碱形式存在。任选地，可使用其药学上可接受的盐或水合物。上文所示的核心结构为具体的HKI-272化合物，称为HKI-272或奈拉替尼，其具有化学名称[(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲氨基)丁-2-烯酰胺]。
虽然目前不太优选，但可使用另一种HKI-272化合物代替奈拉替尼。“HKI-272化合物″在一个实施方案中是指衍生自上文中所示的奈拉替尼的核心结构的化合物。适当的衍生物可包括例如酯、醚或氨基甲酸盐/酯。这样的HKI-272化合物可具有如下结构：
其中：
R1为卤素；
R2为吡啶基、苯硫基、嘧啶基、噻唑基或苯基，其中R2任选地被至多3个取代基取代；
R3为O或S；
R4为CH3或CH2CH2OCH3；
R5为CH3或CH2CH3；以及
n为0或1。
如本文中所使用的，术语″卤素″是指Cl、Br、I和F。
还包括的是，本文中描述的其他HKI化合物和/或奈拉替尼的药学上可接受的盐、水合物和前药。″药学上可接受的盐和酯″是指，其在药学上是可接受的并且具有期望的药理学性质的盐和酯。此类盐包括例如，当存在于化合物中的酸性质子能够与无机或有机碱反应时可形成的盐。适当的无机盐包括例如，与碱金属或碱土金属例如钠、钾、镁、钙、铝形成的盐。适当的有机盐包括例如，与有机碱例如胺碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等形成的盐以及与可形成N-四烷基铵盐例如N-四丁基铵盐的碱形成的盐。药学上可接受的盐还可包括，通过母体化合物中的碱性部分例如胺与无机酸(例如，盐酸和氢溴酸)和有机酸(例如，乙酸、柠檬酸、马来酸、丙酸、乳酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、苯二甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸以及烷烃-和芳烃-磺酸例如甲磺酸和苯磺酸、萘磺酸、甲苯磺酸、樟脑磺酸)的反应形成的酸加成盐。药学上可接受的盐的其他适当的实例包括但不限于，硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸性磷酸盐、异烟酸盐(isonicotinate)、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、延胡索酸盐、葡糖酸盐、glucaronate、蔗糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐、双羟萘酸盐(即，1，1’-亚甲基-双-(2-羟基-3-萘甲酸盐))；和脂肪酸的盐例如己酸盐、月桂酸盐、肉豆蔻酸盐、棕榈酸盐、硬脂酸盐、油酸盐、亚油酸盐和亚麻酸盐。
药学上可接受的酯包括从存在于本发明的化合物中的羧基、磺酰氧基和膦酰氧基形成的酯，例如具有1至6个碳原子的直链烷基酯或包含1至6个碳原子的支链烷基酯，包括甲酯、乙酯、丙酯、丁酯、2-甲基丙酯和1，1-二甲基乙酯、环烷基酯、烷基芳基酯、苄酯等。当存在两个酸性基团时，药学上可接受的盐或酯可以是单-酸-单-盐或酯或二-盐或酯；并且类似地，当存在超过两个酸性基团时，可盐化或酯化一些或所有此类基团。本文中使用的化合物可以以未盐化(unsalified)或未酯化的形式或以盐化和/或酯化的形式存在，并且此类化合物的命名意欲包括原始(未盐化和未酯化的)化合物和其药学上可接受的盐和酯。同样地，本文中使用的一种或多种化合物可以以超过一种的立体异构形式存在，并且此类化合物的命名意欲包括所有单一的立体异构体和此类立体异构体的所有混合物(无论是消旋的还是未消旋的)。
HKI-272化合物(奈拉替尼是其中的一种)的制备详细地描述于美国专利申请公开案2005/0059678(其通过引用合并入本文)中。也参见美国专利6,288,082、美国专利6,002,008、美国专利6,297,258和美国专利申请公开案2007/0104721，其通过引用合并入本文。这些文献中描述的方法也可用于制备奈拉替尼和/或本文中使用的其他HKI-272和经取代的3-喹啉化合物，因而它们通过引用合并入本文。除了这些文献中描述的方法外，通过引用合并入本文的国际专利公开案WO-96/33978和WO-96/33980描述了可用于制备此类HKI-272化合物的方法。虽然此类方法描述了某些喹唑啉的制备，但它们也可用于制备相应地经取代的3-氰基喹啉，因而它们通过引用合并入本文。
术语“治疗”或“疗法”是指，给受试者施用奈拉替尼以预防或延迟、减轻或阻止或抑制与肿瘤相关的症状或病状的发展。
曲妥珠单抗，以及制造和配制其的方法已得到描述。参见，例如，美国专利6,821,515；美国专利6,399,063和美国专利6,387,371。曲妥珠单抗可在名称“赫赛汀(Herceptin)”下从Genentech商购获得。如本文中所使用的，术语“曲妥珠单抗”包括曲妥珠单抗以及曲妥珠单抗的改变的形式和衍生物。术语“曲妥珠单抗”包括这样的试剂，其靶向Her-2受体上与被曲妥珠单抗靶向的表位相同的表位。从H.S.Cho等人，Structure of the extracel lular region of HER2alone andin complex with the Herceptin Fab，Nature 421(2003)，pp.756-760获知该表位。
如本文中所使用的，扩增/过表达erB-2(与Her-2和neu可互换使用)的肿瘤包括某些乳腺癌和其他肿瘤，其可包括卵巢癌、膀胱癌、胃癌、胰腺癌、结肠直肠癌、前列腺癌及肺癌，包括非小细胞肺癌。其中表达或过表达ErbB1的其他肿瘤包括多种人实体瘤，包括非小细胞肺癌(NSCL)、前列腺癌、乳腺癌、结肠直肠癌和卵巢癌。用于筛查样品以确定肿瘤是否过表达erb-1和/或erB-2/Her-2的方法对于本领域技术人员来说是已知的。
基本和辅助抗肿瘤治疗
如本文中所定义的，基本治疗是在确诊肿瘤例如过表达/扩增HER-2/neu的肿瘤后给患者提供的初始治疗(initial therapy)。基本治疗也称为限定性局部治疗(definitive local therapy)。用于过表达/扩增HER-2/neu的肿瘤的基本治疗包括手术(在乳腺癌的情况下，这可包括病灶切除术、改良的根治性乳房切除术、乳房切除术)和/或辐射(单独地或组合地)。辅助治疗是指在初始或基本治疗后常规地提供以增加治愈可能性的治疗。目前，用于过表达/扩增HER-2/neu的肿瘤的标准辅助治疗包括例如，化学治疗和/或抗体治疗。通常，如果在基本治疗(例如，手术)之前递送一个或多个此类辅助治疗，其被称为新辅助治疗。在本说明书的整个下面部分中，术语“新/辅助”用作表示新辅助治疗和标准辅助治疗的简写(shorthand)。可共同递送一个或多个类型的辅助治疗。
在一个实施方案中，患者可以已经历包括递送蒽环类抗生素或紫杉烷或任何环磷酰胺、氨甲蝶呤和5-氟尿嘧啶方案的化学治疗。此类化学治疗可包括下列的一种或多种：蒽环类抗生素例如多柔比星、环磷酰胺、紫杉酚、多西他赛和卡铂。另一种适当的新/辅助治疗是基于多模式蒽环类抗生素的治疗。其他新/辅助治疗包括拉帕替尼(Lapatinib)[二甲苯磺酸拉帕替尼，
]、帕妥珠单抗[Roche，Genentech]、贝伐单抗[
Genentech]、曲妥珠单抗-DM-1[Genentech]等等。新辅助治疗或辅助治疗的选择不是对本发明的限制。本发明的扩展辅助治疗在完成利用曲妥珠单抗的治疗后开始。通常在完成化学治疗后或与之同时递送曲妥珠单抗，作为维持治疗。关于曲妥珠单抗，包括单剂量和多剂量。在一个实施方案中，在第1天以90分钟静脉内输注施用在约4-5mg/kg的范围内的单个负荷剂量的曲妥珠单抗，然后从第8天开始每周施用约2mg/kg。通常，3周为一个周期。可在周期之间提供1至2至3周的间隔。在另一个实施方案中，使用8mg/kg作为负荷剂量和6mg/kg作为维持剂量，按照每3周的给药方案递送曲妥珠单抗。还可以以6mg/kg的剂量提供曲妥珠单抗，每3-4周1次。还可设计和利用其他曲妥珠单抗给药方案。
在一个实施方案中，患者可以已接受基本治疗以及除了曲妥珠单抗新/辅助治疗外，还已接受其他新/辅助治疗。在一个实施方案中，可在扩展辅助治疗过程中在完成曲妥珠单抗治疗后继续进行一个或多个辅助治疗。适当地，在开始本发明的扩展奈拉替尼方案之前，基本治疗和新/辅助治疗都不包括奈拉替尼治疗。
本发明的扩展奈拉替尼方案
在一个实施方案中，在基本治疗开始后约1年、约2年或约3年开始本文中描述的扩展奈拉替尼方案。在完成利用曲妥珠单抗的新/辅助治疗后开始扩展奈拉替尼辅助方案。
可在至少1个剂量、至少3周的周期、至少3个3周的周期、至少4个月、至少6个月、至少8个月或至少1年的曲妥珠单抗新/辅助治疗完成后开始本文中描述的扩展方案。在一个实施方案中，在完成曲妥珠单抗治疗后至少约2周、至少约1个月、至少约6个月、至少约9个月或至少约1年至4年开始扩展奈拉替尼方案。
如本文中描述的，扩展奈拉替尼方案用于减少患者的过表达/扩增HER-2/neu的乳腺癌的复发率。可在治疗开始后，在6个月、1年、3年或5年的时间点上测量这些复发率。该方案包括在基本治疗和新/辅助治疗后给这些患者提供奈拉替尼。在另一个实施方案中，扩展的奈拉替尼用于改善癌症患者的无侵袭性疾病存活、DFS-DCIS、无远处疾病存活和/或远处复发的时间。
本发明的扩展辅助治疗可以只包括在曲妥珠单抗治疗完成后的单个剂量的奈拉替尼。然而，在另一个实施方案中，在1个月、2个月、至少6个月、至少1年、至少18个月的时期内或根据需要或期望，在更长的时期内施用扩展奈拉替尼方案。在另一个实施方案中，用奈拉替尼治疗患者，进行约8个月至约5年，约12个月(1年)至约3年，或进行更长或更短的时期，如由医学专业人员确定的。
如本文中所使用的，就提供奈拉替尼而言，术语“提供”意指直接施用化合物或组合物，或施用可在体内形成有效量的奈拉替尼化合物的前药、衍生物或类似物。
如本文中所使用的以及除非另外指出，术语“个体”、“受试者”和“患者”可互换使用，并且是指任何动物，包括哺乳动物，优选小鼠、大鼠、其他啮齿类动物、兔、狗、猫、猪、牛、羊、马、非人灵长类动物和人。期望地，术语“个体”、“受试者”或“患者”是指人。在大多数实施方案中，受试者或患者需要治疗性治疗。因此，如本文中所用的，术语“受试者”或“患者”意指可对其施用所请求保护的方案的任何哺乳动物患者或受试者。
如本文中所使用的，术语“有效量”或“药学有效量”，当给受试者施用以治疗肿瘤时，足以抑制、减缓、减少或消除受试者的损伤或肿瘤生长，或抑制、减缓或减少疾病的进展和/或增加受试者的无进展存活率。
可以例如以约0.01至100mg/kg的剂量范围口服施用奈拉替尼(或所选择的HKI-272化合物)。在一个实施方案中，以约0.1至约90mg/kg的剂量范围施用奈拉替尼。在另一个实施方案中，以约1至约80mg/kg的剂量范围施用奈拉替尼。在其他实施方案中，以约10至约70mg/kg的剂量范围施用奈拉替尼。在另一个实施方案中，以约15至约60mg/kg的剂量范围施用奈拉替尼。在其他实施方案中，在施用其的周期内的天中，以每天约20至约240mg的剂量范围，以至少约40mg、至少约120mg或至少约160mg施用奈拉替尼。本领域技术人员可常规地进行经验活性测试来测定化合物在生物测定中的生物学活性，从而确定当通过另一种途径递送化合物时施用的剂量。
在一个实施方案中，奈拉替尼的口服剂量为至少约700mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约800mg/周至至少约1700mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约840mg/周至约1680mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约900mg/周至约1600mg/周。在其他实施方案中，奈拉替尼的口服剂量为约1000mg/周至约1500mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约1100mg/周至约1400mg/周。在其他实施方案中，奈拉替尼的口服剂量为约1200mg/周至约1300mg/周。精确的剂量由施用医生基于对要治疗的个体受试者的经验来确定。其他剂量方案和变型是可预见的，并且通过医生指导来确定。
对于奈拉替尼，期望化合物以单位剂量形式存在。可以以约0.01至100mg/kg的剂量范围或以0.1至10mg/kg的剂量范围来施用奈拉替尼。在一个实施方案中，每天1至6次，更常见地每天1至4次口服施用奈拉替尼。适当的单位剂量形式包括片剂、胶囊剂和药囊或小瓶中的粉剂。此类剂量单位形式可包含0.1至300mg奈拉替尼，2至100mg，以120mg至300mg/天，240mg/天的剂量。可选地，可通过另一种适当的途径例如静脉内途径施用奈拉替尼。在另一个实施方案中，每周1次施用奈拉替尼。在某些情况中，可在治疗过程中延迟或中断利用奈拉替尼的剂量给药，进行一段短暂的时间(例如，1、2或3周)。这样的延迟或中断在治疗过程中可发生1次或多次。有效量对于本领域技术人员来说是已知的；其也取决于化合物的形式。本领域技术人员可常规地进行经验活性试验以确定化合物在生物测定中的生物学活性，从而确定施用的剂量。
在一个实施方案中，本文中使用的药物载体的适当实例包括但不限于，赋形剂、稀释剂、填充剂、崩解剂、润滑剂和可用作载体的其他试剂。术语“药学上可接受的赋形剂”意指可用于制备通常为安全的、无毒性的和期望的药物组合物的赋形剂，并且包括对于兽医用途以及人药物用途是可接受的赋形剂。此类赋形剂可以为固体、液体、半固体或在气雾剂组合物的情况下，为气体。按照可接受的制药方法，例如Remingtons Pharmaceutical Sciences，第17版，ed.Alfonoso R.Gennaro，Mack Publishing Company，Easton，Pa.(1985)中描述的方法，制备药物组合物。药学上可接受的载体是与制剂中的其他成分相容并且为生物学上可接受的载体。用于片剂或小胶囊(caplet)制剂的适当的药学上可接受的赋形剂或载体包括例如，惰性赋形剂例如乳糖、碳酸钠、磷酸钙或碳酸钙；粒化剂和崩解剂例如玉米淀粉或海藻酸；粘合剂例如明胶或淀粉；润滑剂例如硬脂酸镁、硬脂酸或滑石；防腐剂例如4-羟基苯甲酸乙酯或丙酯；以及抗氧化剂例如抗坏血酸。可以不包被或包被片剂或小胶囊制剂以改变它们的崩解作用和随后活性成分在胃肠道内的吸收，或改善它们的稳定性和/或外观，使用本领域内公知的常规的包衣衣料(coating agent)和方法。
在一个实施方案中，本发明提供了用于治疗过表达/扩增HER-2/neu的癌症的扩展方案，其包括将扩展的奈拉替尼治疗过程递送给过表达/扩增HER-2/neu的癌症患者。此类扩展治疗包括在完成手术和/或辅助治疗时开始奈拉替尼治疗。该扩展治疗用于提供改善的无侵袭性疾病存活和/或改善总存活、远处复发的时间和无远处疾病存活。
如本文中所描述的，在初始治疗开始后至少1年、至少2年或至少3年，开始扩展的奈拉替尼方案。在一个实施方案中，在基本治疗和标准新/辅助治疗完成后至少约2周和直至约4年，开始奈拉替尼治疗。
在一个实施方案中，可将所选择的伴随治疗与扩展奈拉替尼方案结合使用。例如，患者可进一步经历利用用于骨质减少(osteopenia)或骨质疏松症的双磷酸盐类的伴随治疗。在另一个实例中，患者可进一步经历伴随内分泌治疗。任选地，此类伴随治疗可以是非辅助治疗，而是用于治疗患者可能患有的其他病状或症状。
药物包装/试剂盒
本发明包括包含用于一个个体哺乳动物的抗肿瘤治疗过程的产品或药物包装，其包括一个或多个容器，所述容器具有1、1至4或更多个单位的奈拉替尼和任选地1、1至4或更多个单位的另一种活性剂。
在另一个实施方案中，药物包装包括用于一个个体哺乳动物的抗肿瘤治疗过程(疗程)，其包括具有以单位剂量形式存在的雷帕霉素单位的容器、具有奈拉替尼单位的容器和任选地，具有另一种活性剂的容器。
在某些实施方案中，本发明的药物组合物以可即时施用的形式存在于包装中。在其他实施方案中，本发明的组合物以浓缩的形式存在于包装中，任选地与制备用于施用的终溶液所需的稀释剂一起。在其他实施方案中，产品包括以固体形式存在的用于本发明的化合物和任选地单独的容器，所述容器具有用于本发明中使用的化合物的适当的溶剂或载体。
在其他实施方案中，上述包装/试剂盒包括其他成分，例如产品的稀释、混合和/或施用的说明书、其他容器、注射器、针头等。其他此类包装/试剂盒成分对于本领域技术人员来说是很显然的。
下列实施例举例说明了本发明的组合的用途。可容易地理解，可因本领域技术人员已知的理由，对例如成分的配制、递送途径和剂量进行改变或变动。
实施例
已在患有转移性erbB-2阳性乳腺癌的受试者的2期试验中研究了用作单一试剂的奈拉替尼。将66个具有在先的基于曲妥珠单抗的治疗的受试者招募进入组A(Arm A)；将70个不具有任何在先的曲妥珠单抗暴露的受试者招募进入组B。客观应答率和中位无进展存活用于评估抗肿瘤活性。
根据基于独立的放射学评估的初步数据，在具有在先的曲妥珠单抗治疗的受试者中，总应答率(ORR)为26％(95％置信指数(confidenceindex，CI))并且中位无进展存活(PFS)为23周(95％CI)。对于先前未暴露于曲妥珠单抗的受试者，ORR为57％(95％CI)并且中位PFS为40周(95％CI)。组A中的抗肿瘤活性提供了在曲妥珠单抗难治性受试者中测试用作单一试剂的奈拉替尼的基础。
在组A中，曲妥珠单抗暴露的中位持续时间为60周。受试者中的28个(28％)接受曲妥珠单抗作为辅助或新辅助治疗。大部分受试者(48％)在转移背景中接受一个基于曲妥珠单抗的方案，并且约43％接受第二或第三基于曲妥珠单抗的方案以治疗转移性疾病。组A受试者也进行了多方面的在先的细胞毒性治疗，53％的受试者接受了2-3个在先的方案，并且另外27％接受了超过3个在先的细胞毒性方案。合起来考虑，这些治疗特征描述了组A中被高强度预治疗的并且可能难治的研究群体。因此，难治性群体的26％的ORR表明，奈拉替尼可能是用于erbB-2阳性乳腺癌的高活性试剂。
与奈拉替尼相关的主要不利事件是腹泻，这通常可通过药物治疗、治疗中断或剂量改变来良好、轻易地控制。其他常见的不利事件是恶心、呕吐、疲劳和食欲减退。
实施例1
在随机化、双盲、以安慰剂为对照的3期试验中，在患有早期过表达/扩增HER-2/neu的乳腺癌的妇女中在曲妥珠单抗治疗之后，比较奈拉替尼与安慰剂。受试者必须已完成在先的辅助曲妥珠单抗治疗过程。如果已提供短于12个月的曲妥珠单抗，则必须已提供至少8次在先的剂量，并且必须指定，所述受试者没有资格或不能接受进一步的利用曲妥珠单抗的辅助治疗。在完成在先的辅助治疗过程(包括至少8次，优选12个月的曲妥珠单抗)后，受试者有资格用本文中描述的方案进行治疗。曲妥珠单抗的最后剂量必须在随机化开始前＞2周并且＜4年提供。随机化将通过下列因素分层：ER和/或PgR阳性对ER和PgR阴性；淋巴结状况(nodal status)(0、1-3、4或更多)；距离确诊＜3年或＞3年；与化学治疗顺次提供的曲妥珠单抗对与化学治疗同时提供的曲妥珠单抗。
以1∶1的比例将有资格的受试者随机分配入下列两个组之一：每天奈拉替尼240mg，进行1年或每天安慰剂，进行1年。在中断研究治疗后，继续跟踪受试者的疾病复发和存活，直至获得无侵袭性疾病存活(IDFS)事件的计划数目，并且继续跟踪受试者之后的存活直至研究结束。可使用分层时序检验分析IDFS的主要功效终点(primary efficacyendpoint)和时间-对-事件第二终点。可利用分层Cox比例风险回归模型[DR Cox，1972，“Regression Models and Life Tables(withDiscussion)”，Journal of the Royal Statistical Society，SeriesB 34：187-220]产生危害比和相应的95％置信区间。可使用Kaplan-Meier法[Kaplan，E.L.和Meier，Paul.″Nonparametricestimation from incomplete observations.″J.Am.Stat.Assoc.53，457-481(1958)]评估事件的中位时间和相关的95％置信区间。为了治疗群体(定义为随机化的所有受试者)，进行主要功效分析。按治疗组概述了安全群体(定义为被剂量给予奈拉替尼或安慰剂的所有受试者)的不利事件和严重的不利事件。也概述了3级或更高级腹泻的发病率，并且使用Mantel-Haenszel检验测试了治疗组间的差异。[Mantel N&Haenszel W.Statistical aspects of the ana lysis of data fromretrospective studies of disease.J.Nat.Cancer Inst.22：719-48，1959]。
本说明书中引用的所有出版物通过引用合并入本文。虽然已参考具体实施方案描述了本发明，但应当理解，可进行变动而不背离本发明的精神。此类变动意欲落在所述权利要求的范围内。
Claims (20)
1.用于治疗过表达/扩增HER-2/neu的癌症的方案，其包括在曲妥珠单抗治疗完成后将奈拉替尼治疗递送至过表达/扩增HER-2/neu的癌症患者。
2.权利要求1的方案，其中奈拉替尼治疗过程包括用奈拉替尼治疗癌症患者至少1个月。
3.权利要求1的方案，其中奈拉替尼治疗过程在8个月至5年的范围内。
4.权利要求2的方案，其中所述癌症患者用奈拉替尼治疗至少约12个月。
5.权利要求1的方案，其中所述奈拉替尼治疗在手术和标准辅助治疗完成后约2周至约1年开始。
6.权利要求1的方案，其中口服递送奈拉替尼。
7.权利要求6的方案，其中以片剂形式递送奈拉替尼。
8.权利要求1的方案，其中每天施用奈拉替尼。
9.权利要求1的方案，其中以每天120mg至300mg的剂量递送奈拉替尼。
10.权利要求9的方案，其中以240mg的剂量递送奈拉替尼。
11.用于改善患者的无侵袭性疾病存活(IDFS)或无疾病存活(DFS)-原位导管癌(DCIS)和/或改善总存活、远处复发的时间和/或无远处疾病存活的方法，所述方法包括在曲妥珠单抗治疗后将奈拉替尼递送至所述患者。
12.权利要求11的方法，其中所述患者已接受至少3个周期的曲妥珠单抗。
13.权利要求12的方法，其中所述患者已接受12个周期的曲妥珠单抗。
14.权利要求11的方法，其中所述患者已接受了由曲妥珠单抗和一种或多种化学治疗组成的标准辅助治疗。
15.权利要求14的方法，其中所述化学治疗包括下列中的一种或多种：多柔比星、环磷酰胺、紫杉酚、多西他赛、卡铂、拉帕替尼、帕妥珠单抗、贝伐单抗、曲妥珠单抗-DM-1或基于蒽环类抗生素的治疗。
16.用于改善无侵袭性疾病存活、无疾病存活-原位导管癌、总存活、远处复发的时间和/或无远处疾病存活的方案，其包括用奈拉替尼治疗癌症患者至少1个月至6个月，其中所述利用奈拉替尼的治疗在利用曲妥珠单抗的辅助治疗之后。
17.权利要求16的方案，其中所述患者用奈拉替尼治疗至少12个月。
18.权利要求16的方案，其中所述奈拉替尼治疗在曲妥珠单抗治疗完成后约2周至约4年开始。
19.权利要求16的方案，其中所述奈拉替尼治疗在曲妥珠单抗治疗完成后约6个月至约12个月开始。
20.权利要求16的方案，其中所述患者进一步经历选自下列的一种或多种的伴随治疗：用于骨质减少或骨质疏松症的双磷酸盐类和内分泌治疗。
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